Soluble amyloid-β (Aβ) oligomers may contribute to learning and memory deficits in Alzheimer's disease (AD) by inhibiting N-methyl-D-aspartic acid (NMDA) receptor (NMDAR)-dependent long-term potentiation (LTP), a process widely considered to underlie memory formation. In AD, hippocampal levels of NMDAR subunits are reduced5, and protein levels and phosphorylation status of NMDAR subunits NR1, NR2A, and NR2B correlate with cognitive performance. Human amyloid precursor protein (hAPP) transgenic mice with high levels of Aβ oligomers in the brain also have reduced hippocampal levels of tyrosine-phosphorylated NMDARs and key components of NMDAR-dependent signaling pathways. Notably, AD patients and hAPP mice have hippocampal depletions of the receptor tyrosine kinase EphB2, which regulates NMDAR trafficking and function through direct interaction with NMDARs and Src-mediated tyrosine phosphorylation. EphB2 regulates NMDAR-dependent Ca2+ influx and downstream transcription factors involved in long-term potentiation (LTP) formation, such as Fos, which is depleted in the dentate gyrus (DG) of hAPP mice.